bims-unfpre 2024-10-27 papers

Issue of 2024–10–27
three papers selected by
Susan Logue, University of Manitoba

J Biol Chem. 2024 Oct 19. pii: S0021-9258(24)02411-6. [Epub ahead of print] 107909

Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells.

Sumire Ishida-Ishihara, Kan Yaguchi, Sena Miura, Ryoto Nomura, QiJiao Wang, Koya Yoshizawa, Kimino Sato, Guang Yang, Krisztina Veszelyi, Gabor Banhegyi, Eva Margittai, Ryota Uehara.

Mammalian somatic cells are generally unstable in the haploid state, resulting in haploid-to-diploid conversion within a short time frame. However, cellular and molecular principles that limit the sustainability of somatic haploidy remain unknown. In this study, we found the haploidy-linked vulnerability to ER stress as a critical cause of haploid intolerance in human somatic cells. Pharmacological induction of ER stress selectively induced apoptosis in haploid cells, facilitating the replacement of haploids by co-existing diploidized cells in a caspase-dependent manner. Biochemical analyses revealed that unfolded protein response (UPR) was activated with similar dynamics between haploids and diploids upon ER stress induction. However, haploids were less efficient in solving proteotoxic stress, resulting in a bias toward a proapoptotic mode of UPR signaling. Artificial replenishment of chaperone function substantially alleviated the haploidy-linked upregulation of proapoptotic signaling and improved haploid cell retention under tunicamycin-induced ER stress. These data demonstrate that the ER stress-driven haploid instability stems from inefficient proteostatic control that alters the functionality of UPR to cause apoptosis selectively in haploids. Interestingly, haploids suffered a higher level of protein aggregation even in unperturbed conditions, and the long-term stability of the haploid state was significantly improved by alleviating their natural proteotoxicity. Based on these results, we propose that the haploidy-specific vulnerability to ER stress creates a fundamental cause of haploid intolerance in mammalian somatic cells. Our findings provide new insight into the principle that places a stringent restriction on the evolution of animal life cycles.

Keywords: ER stress; Ploidy; cell death; proteostasis

DOI: https://doi.org/10.1016/j.jbc.2024.107909

Cell Death Discov. 2024 Oct 24. 10(1): 451

Deciphering the nexus between long non-coding RNAs and endoplasmic reticulum stress in hepatocellular carcinoma: biomarker discovery and therapeutic horizons.

Himanshi Goyal, Sachin Parwani, Jyotdeep Kaur.

Hepatocellular carcinoma (HCC) remains a significant global health challenge with few effective treatment options. The dysregulation of endoplasmic reticulum (ER) stress responses has emerged as a pivotal factor in HCC progression and therapy resistance. Long non-coding RNAs (lncRNAs) play a crucial role as key epigenetic modifiers in this process. Recent research has explored how lncRNAs influence ER stress which in turn affects lncRNAs activity in HCC. We systematically analyze the current literature to highlight the regulatory roles of lncRNAs in modulating ER stress and vice versa in HCC. Our scrutinization highlights how dysregulated lncRNAs contribute to various facets of HCC, including apoptosis resistance, enhanced proliferation, invasion, and metastasis, all driven by ER stress. Moreover, we delve into the emerging paradigm of the lncRNA-miRNA-mRNA axis, elucidating it as the promising avenue for developing novel biomarkers and paving the way for more personalized treatment options in HCC. Nevertheless, we acknowledge the challenges and future directions in translating these insights into clinical practice. In conclusion, our review provides insights into the complex regulatory mechanisms governing ER stress modulation by lncRNAs in HCC.

DOI: https://doi.org/10.1038/s41420-024-02200-2

Autophagy. 2024 Oct 20. 1-2

Nuclear proteasomes as a backup for autophagy: interconnected proteostasis pathways.

Meiyan Jin, Daniel J Klionsky.

Protein homeostasis (proteostasis) refers to the balance of the cellular protein environment, tightly regulated by pathways governing protein synthesis, folding, trafficking, and degradation. Growing evidence supports the interconnection of these pathways to ensure the robustness of the proteo-stasis network. A recent study by Park et al. showed that, in macroautophagy/autophagy-deficient cells, the loss of proteasome or nuclear pore components causes synthetic lethality, as cytoplasmic proteins that accumulate under impaired autophagy are transported to the nucleus and degraded by nuclear proteasomes. The authors illustrated the mechanistic basis for why cells with conditions such as Huntington disease, where both autophagy and cytoplasm-to-nuclear shuttling are compromised, are more vulnerable to proteostasis perturbation.Abbreviation: UPR: unfolded protein response; UPS: ubiquitin-proteasome system.

Keywords: Autophagy; nuclear pore complex; nuclear proteasome; proteasome; proteostasis

DOI: https://doi.org/10.1080/15548627.2024.2416261